Intravenous Thyrotropin-Releasing Hormone in Patients with Amyotrophic Lateral Sclerosis: Dose-Response and Randomized Concurrent Placebo-Controlled Pilot Studies

Brooks, Benjamin Rix; Sufit, Robert; Montgomery, George K.; Beaulieu, Debra A.; Erickson, L.

doi:10.1016/s0733-8619(18)30939-3

Cited by 30 publications

(6 citation statements)

References 23 publications

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“…The circled numbers refer to the following drugs. DM235 ( Ghelardini et al ., 2002 ); CG370 ( Ogasawara et al ., 1995 ); Cyclo (pro‐gly) ( Seredenin et al ., 2002 ); TRH ( Brooks et al ., 1987 ); ( Abou‐Khalil et al ., 2003 ; Brooks et al ., 1987 ; De Reuck & Van Vleymen, 1999 ; Devinsky & Elger, 2003 ); Piracetam ( Koskiniemi et al ., 1998 ; De Reuck & Van Vleymen, 1999 ; Genton et al ., 1999 ); Aniracetam ( Spignoli & Pepeu, 1987 ); L ‐Pyroglutamate ( Spignoli et al ., 1987 ); L060 ( Noyer et al ., 1995 ). The in vivo potencies of the drugs were obtained from literature reports of the i.p.…”

Section: Discussionmentioning

confidence: 99%

Piracetam and TRH analogues antagonise inhibition by barbiturates, diazepam, melatonin and galanin of human erythrocyte D‐glucose transport

Naftalin

Cunningham

Afzal-Ahmed

2004

British J Pharmacology

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1 Nootropic drugs increase glucose uptake into anaesthetised brain and into Alzheimer's diseased brain. Thyrotropin-releasing hormone, TRH, which has a chemical structure similar to nootropics increases cerebellar uptake of glucose in murine rolling ataxia. This paper shows that nootropic drugs like piracetam (2-oxo 1 pyrrolidine acetamide) and levetiracetam and neuropeptides like TRH antagonise the inhibition of glucose transport by barbiturates, diazepam, melatonin and endogenous neuropeptide galanin in human erythrocytes in vitro. 2 The potencies of nootropic drugs in opposing scopolamine-induced memory loss correlate with their potencies in antagonising pentobarbital inhibition of erythrocyte glucose transport in vitro (Po0.01). Less potent nootropics, D-levetiracetam and D-pyroglutamate, have higher antagonist K i 's against pentobarbital inhibition of glucose transport than more potent L-stereoisomers (Po0.001).3 Piracetam and TRH have no direct effects on net glucose transport, but competitively antagonise hypnotic drug inhibition of glucose transport. Other nootropics, like aniracetam and levetiracetam, while antagonising pentobarbital action, also inhibit glucose transport. Analeptics like bemigride and methamphetamine are more potent inhibitors of glucose transport than antagonists of hypnotic action on glucose transport. 4 There are similarities between amino-acid sequences in human glucose transport protein isoform 1 (GLUT1) and the benzodiazepine-binding domains of GABA A (gamma amino butyric acid) receptor subunits. Mapped on a 3D template of GLUT1, these homologies suggest that the site of diazepam and piracetam interaction is a pocket outside the central hydrophilic pore region. 5 Nootropic pyrrolidone antagonism of hypnotic drug inhibition of glucose transport in vitro may be an analogue of TRH antagonism of galanin-induced narcosis .

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Section: Discussionmentioning

confidence: 99%

Piracetam and TRH analogues antagonise inhibition by barbiturates, diazepam, melatonin and galanin of human erythrocyte D‐glucose transport

Naftalin

Cunningham

Afzal-Ahmed

2004

British J Pharmacology

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“…One chronic study of intravenous administration of high dose TRH for 10 weeks demonstrated statistically significant differences compared to baseline in the increased or maintenance of strength or function in TRH -treated patients with ALS. 7 This study will have to be confirmed employing the same principles just defined in the planning of additional clinical trials of TRH or TRH analogues. Exercise capacity as fraction of baseline.…”

Section: Effect Of Chronic Intravenous Trh Treatmentmentioning

confidence: 96%

“…86 Another small parallel placebo-controlled study of intravenous administration of 10 mg/kg TRH showed significant differences between treated and placebo-treated patients in bulbar and lower extremity tests over the course of 10 weeks oftherapy. 7 Three analogues of TRH have been tested in controlled studies. 25-27.32.~No specific change was found in controlled trials of CG3509 or MK-771.…”

Section: Intravenous Administrationmentioning

confidence: 99%

A Summary of the Current Position of TRH in ALS Therapy

Brooks¹

1989

Ann NY Acad Sci

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The critical points that must be addressed in evaluating ergotropic drugs are exemplified by the current morass of positive and negative results that have been obtained in clinical investigations of TRH or its analogues. Appropriate subject selection is crucial. These patients may have bulbar symptoms, and those features of ALS should be specifically assayed for treatment effects relative to placebo. Gender-specific effects of TRH need to be accounted for in study design. In addition, electrophysiological techniques such as single fiber density may help determine the responsiveness of patients to TRH or its analogues. The clinical significance of an increase in fiber density following TRH or other drugs should be determined, as it will provide insight into the state of motor neurons in the spinal cord of patients with ALS and possibly could be important in determining those who may respond to TRH if such a response is possible. Clinical studies have quite clearly shown conflicting results. Basic studies, however, have shown that response to TRH is state dependent, that is, whether the patient is male or female. Clinical studies have shown that response to TRH is state dependent, that is, it depends on whether the patient has bulbar or nonbulbar signs and is male or female. Future studies must take into consideration this state dependence as a specific feature of the pharmacological action of TRH and its analogues.

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“…Its synthetic analogs, i.e., Protirelin and Taltirelin hydrate, have been used to treat epilepsy, spinal cord injury, spinocerebellar ataxia, and neonatal respiratory distress (Shimizu et al, 1989;Tzeng et al, 2000;Urayama et al, 2002). Since TRH has been found in the spinal MNs, its role in the pathogenesis of MN diseases has been suggested, even if a TRH-based trial in ALS was unsuccessful (Brooks et al, 1987). However, its beneficial effects on motor functions and electromyographic results of SMA type II/III patients have been reported in different studies (small groups of infants with SMA type I in children with types II and III) and in a clinical trial (Takeuchi et al, 1994;Tzeng et al, 2000;Wadman et al, 2020).…”

Section: Hormone Signaling Pathwaysmentioning

confidence: 99%

Drug Screening and Drug Repositioning as Promising Therapeutic Approaches for Spinal Muscular Atrophy Treatment

et al. 2020

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Intravenous Thyrotropin-Releasing Hormone in Patients with Amyotrophic Lateral Sclerosis: Dose-Response and Randomized Concurrent Placebo-Controlled Pilot Studies

Cited by 30 publications

References 23 publications

Piracetam and TRH analogues antagonise inhibition by barbiturates, diazepam, melatonin and galanin of human erythrocyte D‐glucose transport

Piracetam and TRH analogues antagonise inhibition by barbiturates, diazepam, melatonin and galanin of human erythrocyte D‐glucose transport

A Summary of the Current Position of TRH in ALS Therapy

Drug Screening and Drug Repositioning as Promising Therapeutic Approaches for Spinal Muscular Atrophy Treatment

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